Telomerase reverse transcriptase deficiency as diagnostic marker of myelodysplastic syndrome

Abstract

The subject invention pertains to methods and compositions for the detection and treatment of myelodysplastic syndromes based on impaired telomerase function.

1 . A method for detecting myelodysplastic syndrome (MDS) in a subject, comprising analyzing a biological sample from the subject for telomerase function, wherein an impaired telomerase function is indicative of MDS in the subject. 
     
     
         2 . The method according to  claim 1 , wherein said analyzing comprises determining one or more of the following: TERT transcription (TERT mRNA expression), telomere length, telomerase activity, TERC RNA template, telomerase induction (inducible TERT level), and T-cell receptor excision circles (TREC). 
     
     
         3 . The method according to  claim 1 , further comprising obtaining the biological sample from the subject. 
     
     
         4 . The method according to  claim 1 , wherein the biological sample is whole blood, plasma, or serum. 
     
     
         5 . The method according to  claim 1 , wherein the biological sample comprises peripheral blood T cells. 
     
     
         6 . The method according to  claim 1 , wherein the biological sample comprises CD3+ T cells, and said analyzing comprises analyzing telomerase function in the CD3+ T cells. 
     
     
         7 . The method according to  claim 1 , wherein the MDS is one or more of among refractory cytopenia with unilineage dysplasia (refractory anemia, refractory neutropenia, or refractory thrombocytopenia); refractory anemia with sideroblasts (SARS); refractory anemia with sideroblasts-thrombocytosis (SARS-t); refractory cytopenia with multileneage dysplasia (RCMD) (refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS), including subjects with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia); refractory anemia with excess blasts (RAEB)-I or -II; acute leukemia; myelodysplastic-myeloproliferative overlap syndrome; 5q-syndrome; unclassifiable myelodysplasia; or refractory cytopenia of childhood (dysplasia in childhood). 
     
     
         8 . The method according to  claim 1 , wherein the MDS is refractory cytopenia with multilineage dysplasia (RCMD), refractory anemia with excess blasts-1 (RAEB-1), or refractory anemia with excess blasts-2 (RAEB-2). 
     
     
         9 . (canceled) 
     
     
         10 . The method according to  claim 1 , wherein said analyzing comprises measuring telomerase function in the biological sample and comparing the measured level of telomerase function to a reference level of telomerase function. 
     
     
         11 . (canceled) 
     
     
         12 . The method according to  claim 1 , wherein the subject has previously been treated for MDS, and telomerase function is analyzed to monitor the status of the MDS in the subject and/or effectiveness of the treatment. 
     
     
         13 . A method for treatment of myelodysplastic syndrome (MDS) in a subject determined to have MDS, comprising administering a therapeutic treatment to the subject, wherein the subject has been determined to have MDS based on impaired telomerase function. 
     
     
         14 . The method according to  claim 13 , wherein said method comprises qualitatively or quantitatively analyzing a biological sample from the subject for telomerase function, wherein an impaired telomerase function is indicative of the presence of MDS in the subject; and treating the subject if the subject is determined to have MDS. 
     
     
         15 . The method according to  claim 14 , wherein said analyzing comprises determining one or more of the following: TERT transcription (TERT mRNA expression), telomere length, telomerase activity, TERC RNA template, telomerase induction (inducible TERT level), and T-cell receptor excision circles (TREC). 
     
     
         16 - 21 . (canceled) 
     
     
         22 . A method for monitoring myelodysplastic syndrome (MDS) in a subject post-treatment, comprising administering a treatment for the MDS to the subject; and analyzing a biological sample from the subject for telomerase function, wherein the biological sample is obtained from the subject post-treatment, and wherein an impaired telomerase function in the biological sample is indicative of MDS in the subject. 
     
     
         23 . A composition comprising an array or panel for detection of myelodysplastic syndrome (MDS), comprising: (a) one or more moieties that can bind specifically to one or more proteins, or nucleic acids encoding said one or more proteins, whose expression is associated with telomerase function. 
     
     
         24 . The composition of  claim 23 , further comprising: (b) one or more moieties that can bind specifically to one or more proteins, or nucleic acids encoding said one or more proteins, whose expression is associated with the presence of a malignancy. 
     
     
         25 . The composition of  claim 23 , wherein said one or more moieties of (a) and/or (b) comprises one or more moieties selected from among an antibody, or an antigen binding fragment of said antibody, a peptide, a nucleic acid, or a ligand. 
     
     
         26 . The composition of  claim 24 , wherein the malignancy is a hematologic malignancy. 
     
     
         27 . The composition of  claim 26 , wherein the hematologic malignancy is MDS. 
     
     
         28 . The composition of  claim 23 , further comprising a substrate, wherein the one or more moieties of (a) and (b) are attached to said substrate. 
     
     
         29 - 30 . (canceled)